Aerosolization is the most dangerous route of infection by select agents. Because of difficulty in diagnosis, it would be valuable to have therapies active against a broad range of aerosolized pathogens. Remarkably, ittle is known about the pathophysiology, microbiology, and immunology associated with aerosol delivery. This is due mostly to infrastructure requirements for aerosolization experiments, the specialized equipment that is necessary, and the limited number of individuals trained in the field of aerobiology. The work proposed in this application addresses this lack of understanding by combining expertise in aerobiology, microbial pathogenesis, immunology, and gene therapy. The ultimate goal of this program is to identify commonalities or deficiencies in host responses that can be targeted by immunotherapies, treatments that would benefit an individual exposed to any number of bioterrorism agents. To address this, three different select agent bacterial pathogens have been chosen for detailed study: Francisella tularensis, Yersinia pestis, and Burkholderia pseudomallei. Each of these pathogens alters host responses, thereby enhancing their success against the host. Bolstering host responses, therefore, is an attractive strategy to mitigate morbidity and mortality by agents like these three pathogens, regardless of the actual bacterium infecting the host. To identify immunotherapies providing cross-pathogen protection against aerosol infection, we propose these specific aims: Aim 1: To characterize the natural history of bacterial select agents delivered by aerosol. The objective of this aim is to characterize the pathophysiology of the three bacterial pathogens aerosolized into mice. Aim 2: To determine shared and distinct innate and bridging immune responses to bacterial select agents. These studies will characterize the innate and bridging immune response to F. tularensis, B. pseudomallei, and Y. pestis. Aim 3: To manipulate early host responses as therapeutic interventions. These studies will investigate whether augmenting innate and/or bridging immune responses with Th1 or Th17 effector cytokines can bolster host resistance to F. tularensis, B. pseudomallei, and Y. pestis delivered as an aerosol.